We have demonstrated that lack or dysfunction of peripheral T cells is associated with impaired learning and aberrant neurogenesis. Moreover, we have revealed that these deficits can be remedied by reconstitution of immune deficient recipients with T cells from wild type donors. We showed that the T cells that patrol the meninges of the brain are central players in neuroimmune interactions that benefit brain function. It has also been widely demonstrated that chronic stress is correlated with gut inflammation and with impairments in learning and neurogenesis. We have addressed, at least partially, what type of immune cells is mediating neuro-immune interactions (T cells), and where (meningeal spaces), although how the changes in peripheral immunity as a result of stress are impacting the brain has not been addressed. Here we aim to provide new insights into these complex interactions. Our overarching hypothesis is that changes in the gut microbiota as a result of stress facilitate changes in the meningeal immune system, which in turn impacts brain function, thus creating a tripartite loop - brain, immune and gut. During the exploratory R21 phase we plan to characterize the interactions between the gut microbiota and meningeal immune cells under chronic stress, by addressing: (1) the phenotype change of meningeal T cells as a result of microbiome alterations during chronic stress; (2) contributions of the immune system vs. vagus nerve to changes in meningeal T cell phenotype; and (3) the molecular signature of blood metabolites as a result of microbiota changes during chronic stress. Successful completion of this phase will determine the underlying mechanistic link between the gut microbiota and the brain via the immune system, vagus nerve stimulation, and/or microbial metabolites. In the second, hypothesis-driven phase, we will test if a defect in Th2 cells is associated with depression. To our knowledge, this is the first attempt to mechanistically link the gut microbiota to brain function by a defined mediating cell type. We expect the gut microbiota to mediate IL-4 production by meningeal T cells in support of brain function and neurogenesis (directly, or via additional cellular mediators).